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More evidence of lack of Vitamin D efficacy for COVID-19 — Two studies

The idea that vitamin D supplements can reduce susceptibility to, and the severity of, COVID-19 is seductive – it offers a simple, elegant solution to a very complex and lethal problem. But, reports The Guardian, analyses encompassing large European datasets suggest the enthusiasm for the sunshine vitamin may be misplaced.

Two still to be peer-reviewed papers looked at the link between vitamin D levels and COVID-19 and both reached the same conclusion: evidence for a direct link between vitamin D deficiency and COVID outcomes is lacking.

One set of researchers at McGill University, Montreal, Kyoto University, Japan, Technion Israel Institute of Technology, University of Siena, Italy and Kings College London, mined a database of hundreds of thousands of mostly white participants to understand whether giving them vitamin D could decrease their probability of having symptomatic or severe COVID.

The Guardian reports that researchers looked at the records of people with certain genetic markers that make them predisposed to vitamin D deficiencies, something that is not influenced by factors such as age and other underlying conditions. They found no evidence for the idea that supplements protect against COVID.

The report says another study compared the prevalence of vitamin D deficiency in 24 European countries to COVID infections, recovery and mortality data. Lead author, Dr Michael Chourdakis, from Aristotle University of Thessaloniki, Greece, said the analysis avoided the methodological limitations of previous studies by only using recent data on vitamin D, and did not only include subsets of the population, for instance, people in nursing homes.

“There is an overloading of information about vitamin D benefits … vitamin D has been praised for too many things,” he said, “even though we have very limited data for that.”
He added that the study was methodologically solid and the data showed no significant correlation between vitamin D and COVID infections, recovery or mortality.

The Guardian reports that those that traditionally exhibit vitamin D deficiency – older adults and minority ethnic populations – are the same groups that have been disproportionately affected by COVID-19. Protracted lockdowns and subsets of the population shielding has also enhanced time spent indoors away from sunlight.

And in general, vitamin D has been implicated in helping the immune response to respiratory infections – so supplements feels like the intuitive answer.

But the evidence on COVID so far – although some of it is positive – is circumstantial.

Meanwhile randomised controlled trials designed to definitively answer whether vitamin D status plays a direct role in COVID infections and outcomes are ongoing. “What we lack at the moment is really a definitive trial which demonstrates a cause and effect relationship,” said Adrian Martineau, a professor of respiratory infection and immunity at Queen Mary University of London, who is leading such a study.


Study details 1
Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics 2 Initiative: A Mendelian randomization study 

Guillaume Butler-Laporte, Tomoko Nakanishi, Vincent Mooser, David R Morrison, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Annarita Giliberti, Alessandra Renieri, Yiheng Chen, Sirui Zhou, Vincenzo Forgetta, J Brent Richards

Published in medRxiv on 7 March 2021

Increased vitamin D levels, as reflected by 25OHD measurements, have been proposed to protect against COVID-19 disease based on in-vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used two-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.
Methods and findings
Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and 1,284,876 without COVID-19, from 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by one standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (OR = 0.97; 95% CI: 0.95, 1.10; P=0.61), hospitalization (OR = 1.11; 95% 92 CI: 0.91, 1.35; P=0.30), and severe disease (OR = 0.93; 95% CI: 0.73, 1.17; P=0.53). 93 We used an additional 6 meta-analytic methods, as well as sensitivity analyses after 94 removal of variants at risk of horizontal pleiotropy and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency.
In this two-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.


Study details 2
Prevalence of vitamin D is not associated with the COVID-19 epidemic in Europe. A judicial update of the existing evidence.

Dimitra Rafailia Bakaloudi, Michail Chourdakis

Published in medRxiv on 7 March 2021

COVID-19 has emerged as a global pandemic, affecting nearly 104 million people worldwide as of February 4th 2021. In previous published studies, the association between the mean Vit D status of each country and COVID-19 infection rate, and mortality among the adult population in European countries was examined. The aim of this study was to re-examine the relationship between the Vit D status of each country and COVID-19 infection, recovery, and mortality using updated data and a different methodological approach.
Information only form the last decade on Vit D concentration/deficiency for each country was retrieved through literature search on PubMed database. As of February, 4th 2021, COVID-19 infections and mortalities per one million population as well as total recoveries were extracted from the Worldometer website. The association between vitamin D deficiency and COVID-19 infection, recovery, and mortality were explored using correlation coefficients and scatterplots.
The prevalence of vitamin D deficiency among European countries ranged from 6·0 (Finland) to 75·5% (Turkey), with several countries facing more than 50% of vitamin D deficiency among their population. Non-significant correlations were observed between the number of COVID-19 infections (r=0·190; p=0·374), recoveries (rs=0·317, p=0·131), and mortalities (r=0·129; p=0·549) per one million population, with the prevalence of vitamin D deficiency.
Prevalence of vitamin D deficiency was not significantly associated with either number of infections, recoveries or mortality rate of COVID-19 among European countries. Thus, it is an important parameter to be considered when implementing preventive measures to face COVID-19.


[link url="https://www.theguardian.com/world/2021/mar/09/vitamin-d-supplements-may-offer-no-covid-benefits-data-suggests"]Full report in The Guardian (Open access)[/link]


[link url="https://www.medrxiv.org/content/10.1101/2020.09.08.20190975v5.full.pdf"]medRxiv study 1 (Open access)[/link]


[link url="https://www.medrxiv.org/content/10.1101/2021.03.04.21252885v1.full.pdf"]medRxiv study 2 (Open access)[/link]



See also MedicalBrief archives:

[link url="https://www.medicalbrief.co.za/archives/covid-19-and-vitamin-d-insufficient-evidence-as-a-treatment-nice-guideline/"]COVID-19 and vitamin D: ‘Insufficient evidence’ as a treatment — NICE Guideline[/link]


[link url="https://www.medicalbrief.co.za/archives/uks-nice-review-not-recommending-vitamin-d-to-reduce-risk-of-covid-19/"]UK’s NICE review not recommending vitamin D to reduce risk of COVID-19[/link]


[link url="https://www.medicalbrief.co.za/archives/still-no-definitive-answer-on-vitamin-d3-to-treat-covid-19/"]Still no definitive answer on Vitamin D3 to treat COVID-19[/link]


[link url="https://www.medicalbrief.co.za/archives/over-80-of-covid-19-patients-have-vitamin-d-deficiency-spain-hospital-study/"]Over 80% of COVID-19 patients have vitamin D deficiency — Spain hospital study[/link]


[link url="https://www.medicalbrief.co.za/archives/vitamin-d-deficiency-may-raise-risk-of-coronavirus-infection-retrospective-study/"]Vitamin D deficiency may raise risk of coronavirus infection — retrospective study[/link]


[link url="https://www.medicalbrief.co.za/archives/covid-19-and-vitamin-d-sa-experts-say-evidence-is-scant/"]COVID-19 and vitamin D: SA experts say evidence is scant[/link]


[link url="https://www.medicalbrief.co.za/archives/vitamin-d-supplementation-no-benefit-in-preventing-treating-covid-19-consensus-paper/"]Vitamin D supplementation: No benefit in preventing/treating COVID-19 — Consensus paper[/link]

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